Abnormal hormonal, nutritional, metabolic or environmental conditions during pregnancy alter the developmental trajectory of the fetus culminating in adult diseases. Exposure of sheep to excess testosterone (T) during fetal life leads to neuroendocrine, ovarian and metabolic defects that parallel the reproductive and metabolic phenotype of women with polycystic ovary syndrome, with postnatal obesity amplifying these defects. Ovarian defects involve increased follicular recruitment and follicular persistence. Ovarian disruptions are evident during fetal life and include increased androgen receptor expression, imbalance in the ratio of estrogen receptor alpha and beta, and altered insulin signaling. Metabolic defects, mediated by androgenic actions ofT, are also evident eariy in fetal life culminating in insulin resistance. Postpubertal treatment with an insulin sensitizer improves insulin sensitivity and prevents further deterioration of reproductive axis implicating a role for insulin. Our recent findings suggest that gestational co-treatment with an androgen antagonist overcomes disruptive effects of prenatal T at the neuroendocrine and ovarian level. Proposed studies will determine the contributing role of prenatal androgen in the programming of prenatal T-induced reproductive pathology and delineate the relative role of postnatal hyperinsulinemia and functional ovarian hyperandrogenism in facilitating the expression of cyclic ovarian disruptions. Specifically, studies will address if attenuation of hyperinsulinemic status beginning before puberty with insulin sensitizers or ovarian hyperandrogenism with an androgen antagonist would overcome follicular persistence and rescue cyclic function in prenatal T-treated sheep and if prevention of androgen action by co-treatment with androgen antagonist during fetal life would prevent programming of metabolic and reproductive pathologies. Ovaries from these interventional studies will be used to 1) address the role of intraovarian steroid and insulin receptor signaling, 2) identify protein clusters mediating prenatal T-induced ovarian dysfunction; and 3) delineate the role of epigenetic modifications in mediating differential protein expressions. Findings from these studies would be of translational relevance to human infertility disorders.